Solutions for the improved nebulization therapy of the lungs and bronchioles



Patented Jan. 28, 1947 SOLUTIONS FOR THE IMPROVED NEBULIZA- TION THERAPY OF THE LUNGS AN BRONCHIOLES Harold Alexander Abramson, New York, N. Y.

No Drawing. Application September 23, 1941,

a Serial No. 411,987

This invention relates to therapeutic agents of the type which are useful for the treatment of the lungs and bronchioles by nebulization (mist or fog formation) in the inhalant therapy of asthma.

One of the objects of the invention is to obtain an improved therapeutic agent producing a more stable mist by nebulization so that it is more readily carried by the respiratory movements into the lungs where it may act upon the bronchioles and other tissues which are responsible for the asthmatic attack with a more effective therapeutic effect because the mist produced by nebulization ismore stable.

Another object is to provide an improved inhalant suitable for nebulization which allows the patient to more readily estimate the dose when used in the inhalant therapy of asthma.

Another object is to produce a therapeutic agent which is effective as an antispasmodic in asthma, which is pleasant in efiect, and of a character as to inhibit oxidations' and the growth of microorganisms which would lead to deterioration.

In the broader aspects of my invention the new therapeutic agent com-prises an aqueous solution of a polyhydroxyl alcohol base (e. g. glycerol; ethylene glycol; propylene glycol), and antispasmodic substance, suflicient preservative to inhibit the growth of microorganisms, as well as an antioxidant, like sodium bisulphite, to diminish the oxidation rate of the antispasmodic.

a solution of about 1% of the alkaloid, but v or 2% may also be employed. In general, a satisfactory amount is the equivalent to 1% of the naturally occurring epinephrine base.

It will be shown that instead of glycerol, ethylene glycol, propylene glycol, and, other substances as well as solids under certain conditions may be r employed to obtain enhanced nebulization.

It is well known to those versed in the art that to prevent bacterial growth in solutions of the type under discussion a preservative like chlorbutanol may be employed.

The primary. antispasmodic substances are epinephrine, amphetamine, ephedrine, neosynephrine 4 Claims. (Cl. 16758) The discovery to be described had its origin ing patients with asthma by means of the nebulization of solutions of epinephrine (adrenalin salts) containing 1% of epinephrine hydrochloride or 1% of epinephrine phosphate (adrenalin and epinephrine are used interchangeably) by the usual method. The usual method consists in the employment of a special device known as a nebulizer and a solution of 1% epinephrine salt which does not embody in its composition the improvements embodied in my invention. The patients complained that they did not know when the nebulizer functioned properly because they could not readily see the mist which disappeared too rapidly to be easily observed. Further, the dosage because of the rapid disappearance of, the mist was uncertain. Psychologically, the technic was therefore disadvantageous and many patients discontinued the use of ordinary aqueous solutions of the material because they were uncertain that a mist was being formed that would have therapeutic value. The method which has subsequently been developed is generally applicable to the nebulization of dissolved substances. in general, as well as epinephrine.

Before discussing the method of producing nebulization it is important to distinguish clearly between an atomizer and a nebulizer. Asidefrom the difierence in the construction of the two (which is readily observable in the usual commercial models) the eifects of the two are quite diii'erent therapeutically. In the nebulization therapy of the lungs and bronchioles to which this invention specifically refers, the size of the nebulized droplets differs from the atomized droplets in that the nebulized droplets are smaller and therefore not as readily observed.

- The effects of each, also, in therapy of the lungs and bronchioles are quite different because the P an atomizer is employed with a 1% solution of epinephrine or concentrations in that vicinity, it produces droplets which are so large that most of the absorption occurs from the mouth, nose, or

throat. Indeed, some may be swallowed leading to unpleasant results because of the local application. The present invention does notdeal with the local application of material of this type but specifically refers to the nebulization therapy of the lungs and bronchioles where the material is carried by convection into the lungs with the inspired air. The problem, therefore, in the treatment of conslstsofgettingvery" small droplets in very large numbers deeply into the lungs so that the anti-spasmodicactivlty of the active drug (e. g. epinephrine) may be eifective. With the use of the nebulizer, the air is drawn in with inspiration and the mist which is formed during successful nebulization is carried with the respiratory" movements of the aipinto the lungs. This movement is essentially"a convection process. When the bulb of an atomizer, however, is suitably compressed, the movement of the droplets of the'spray produced by*the' atomizer is primarily due to the momentum imparted by the blast of air. In the case of the nebulizer, however, the spray should be mistlike or fog-like in character .and it should be carried along with the aircurrents in the manner Potassium chloride in the solid state can not be solution, a complete change occurs in the nature of the nebulization as compared with the solvent alone or with small quantities of these materials. Depending on the concentration, the addition of these substances markedly enhances the ease of nebulization. Mists are formed which have a just described. In other words, the droplet size and the droplet permanence in nebulization should be produced to allow the air inspired to be carried along a sumclent distance and with a suillcient amount of material so that the mistlike or fog-like spray enters the bronchi and bronchioles where it attacks directly the pathological tissues producing the-asthma. For this reason, it is important in treating the lungs in the asthmatic state with a 1% solution of;

epinephrine salt, or concentrations inthat vicinity, to use a nebulizer which produces a me, permanent, mist and to use solutions or modify more permanent character. contain a larger number of visible droplets. Since potassium chloride and sodium chloride do not lower the surface tension but raise the surface tension, it is evident that the surface tension factor need not be important. and that other 1] factors play a more dominant role.

saturating water with potassium chloride at room temperature increased the nebulization with mist formation markedly improved. But

them so that they lend themselves readily to the formation of mists.

With the droplets from ordinary aqueous solunebulization, evaporation is rapid and an insufflcient number are formed-to produce a mist suftions in use in the therapy 'of asthma formed by ficiently permanent .to be readily inspired by the patient.

The problem involved, then, is to produce by I nebulization alarger number of visible particles and to control the droplets during the period of treatment so-that a more permanent mist results with enhanced therapeutic effect. Examination of the thermodynamic equation which deals with.

the evaporationof small droplets discloses that not alone is vapor pressure important in droplet formation and permanence but the radii of the droplets, the density of the material and the surface tension of the droplets are also involved. Because of the large number of variables it is, therefore, difficult if not impossible from a purely theoretical consideration of the theory of mist formation to decide just how all of the-pdrameters could be controlled in the nebulization of epinephrine-salts. An experimental examination of all the parameters separately may be made so that the control of droplet size, number, and stability could be achieved. After suitable experimentation it was decided to scrutinize most care- "fully the rolesplayed by vapor pressure and nuclei formation as well as surface tension in improving the nebulization solutions for the therapy of the lungs and bronchioles.

Experiments considering the effects of substances which would be present in sufiicient ,quantity to lower the vapor pressure of small only a slight increase in the efficiency of nebulization was observed when water was only M saturated with potassium chloride. It is not necessary, therefore, to have a liquid dissolved in the solution which is nebulized but a sufilcient amount of solid non-toxic substances like potassium chloride, the sugars, urea, or salts may be employed with an antispasmodic to relieve the spasmsin the asthmatic state. These substances act-as nuclei for the formation of more perma- .nent mists.

It is important to. note that I have discarded in the nebulization therapy of asthma (and which I shall subsequently show in actual use on patients) the notion that isotonic solutions or solutions nearly isotonic are needed. Prep,- arations' ordinarily used in the therapy of the nose contain isotonic salt solutions or isotonic sugar solutions or the solutions are nearly isotonic. However, these quantities are not suincient to "producethe high degree of nebulization required in the treatment of the lungs with substances like epinephrine salts.

In this invention it is recognized that a. sumciently high concentration of-any one of these substances or of mixtures of these substances introduced can produce improved nebulization and mist formation without the addition of substances like alcohol specifically designed to lower the surface tension.

Evidently when a nebulizer produces a mist under the conditions described in the foregoing droplets (which, as I have pointed out, distill.rap-- 1 idly and disappear) disclosed that substances like potassium chloride, .sodium chloride, triacetin,

monoacetin, ethylene glycol, propylene glycol, urea, sorbitol, dextrose and glycerol in suilicient concentrations increased the nebulization ef-j ficiency of solutions of antispasmodics and led to; improved therapy in the treatment of asthma the: method of nebulization. It is evidentthat with suilicient amount of material addedto produce increased nebulization, the materials being like the sugars, glycerol, etc., or their mixtures, the mist which is produced consists, of water mdroplets which must be small enough to be breathed into the lungs and tiny bronchioles along with the air moving with the body of the air. V 'I'h'e curvature of the droplets being very great, the vapor pressure of. these droplets is probably decreased by theaddition of substances produce a permanent mist which act as stable nuclei containing the active therapeutic agent.

Experiments on patients withasthma over a long period have shown that therapy with 1% epinephrine salt (or concentrations in that These mists also which'lower thevapor pressure and in this way vicinity) administered by nebulization is markedly improved by the addition of from 10% to 50% of glycerineby volume in the solution.

There has been no irritation tothe lungs or any damage to the patient. "'Psychologically. the patients have preferred this new mixture over a long period. Indeed, inone instance, a 50% solution of glycerine plus. 1% epinephrine with the usual preservative and antioxidant has been used by an. asthmatic patient for .four' months with no irritation of the throator lungs. Inaddition, the of j the highlconcentratio'n of glycerine hasa soothingeiiect onthe pharynx andmakes this'vehlcle alsomore d'esirable. Sub-- stances other 'glycerine, in addition to glycerine, may falsobe employed. These-substances, mentioned previously, must be present in s'uflicient concentration to produce a permanent mist. Thus. mixtures of sugar and g ycerine and u ar, or 'glycerine and urea,- may" also be conveniently I In actual practise 50% of g'lycerine has proved very serviceable and has been used extensively by many patients over long periods.

The best results are obtained by using more than 10% of glycerol or its homologs. There is no upper limit physiologically to the concentration of'glycerol which may be used. The upper limit would depend on the ease with which the glycerine'solution is forced through the particular nebuliz'er employed by the patient. Practically, there is nojneed to exceed 50% .of glycerol. The following two formulaeare examples of solutions which have been used.

Epinephrine hydrochloride 'grams Glycerol -cubic centimeters Sodium bisulphite' -..grams Chlor 10.--- 0.4 Water to.... cubic centimeters 100 Epinephrine phosphate (pH 4 to 5) grams 1 Glycerol cubic centimeters 10 Sodium bisuiphite grams- 0.1

Chloretone do 0.4 Water to --cubic centimeters-.. 100

angers concentration of at least 0.5% by weight, in

which solution is dissolved at least 10% by 3 volume of a polyhydric alcohol so as tolower. the vapor pressure of the therapeutic compostl5v tionto a, degree sumcient to stabilize the mist formed on nebulization of said therapeutic composition,

Glycerol '..'..cubic centimeters-.. 10'

Sodium bisulphite grams 0.1 "Chloretone A therapeutic composition adapted for the nebulization therapy of asthma which comprises, an aqueous-solution of an epinephrine salt in a concentration .of at least 0.5% by weight, and glycerol in an amount of at-least 10% by volume of the therapeutic composition, said glycerol serving to stabilize the mist formed on nebulization of said therapeutic composition.

3. A therapeutic composition adapted for the nebulization. therapvof asthma which comprises the following ingredients in thestated amounts or proportions thereof:

Epinephrine hydrochloride grams Glycerol ..cubic centimeters..- Sodium bisulphite gramsr 0.1 Chloretone do 0.4 Water.. cubic centimeters 4. A therapeutic composition adapted for the nebulization therapy of asthma which comprises the following ingredients in the stated amounts or proportions thereof:v

Epinephrine phosphate (pH 4 to 5),.. gralns I 1 ABRAMSON. 

